1. Developing novel approaches to determine the clinical significance of UVs. 2. Developing new clinical guidelines and implement them into clinical practice.
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Following the KGCL protocol (Klinisch Genetisch Centrum Leiden), all the
affected family members of the patient will be tested on the presence of the
Unclassified Variant. Furthermore, also at least one older not affected family
member should be tested. This information helps to understand more about the
association between carrying a variant and developing cancer.
Secondary outcome
Niet applicable.
Background summary
The BRCA1 and BRCA2 genes together make the largest contribution to the
predisposition to hereditary breast and ovarian cancer. The identification of a
disease causing mutation initiates intensive surveillance or risk reducing
surgery in carriers. However, in about 10-20% of the DNA tests gene variants
with an uncertain clinical significance (unclassified variants or UVs) are
identified. The uncertainty of the effect of these variants on protein function
and thus on the estimated cancer risk in UV carriers makes both clinical
surveillance and genetic counseling of patients and their families very
problematic.
Study objective
1. Developing novel approaches to determine the clinical significance of UVs.
2. Developing new clinical guidelines and implement them into clinical
practice.
Study design
1) Although individual UV-related characteristics can be informative, they
rarely provide sufficient information for a definitive classification.
Information will be collected about co-segregation of the UV with cancer in the
family, extent of personal and family history, in-silico analysis, effects on
RNA splicing, morphological and pathological characteristics of tumors, LOH and
array CGH. Subsequently, a multifactorial likelihood-ratio model will be
developed that integrates all available information that is collected regarding
a specific UV. The model will provide an overall odds of causality.
2) The DNA diagnostic laboratories currently use in silico analysis to
categorize UVs into a four-class system with increasing probability of
pathogenicity, and uses this categorization to make clinical recommendations.
This classification system has a subjective element and performs poorly in
assigning a UV to a specific class. Guidelines and a decision aid will be
developed to assist DNA laboratories and genetic counselors in improving and
objectivising the classification and communication of UVs to counselees.
Study burden and risks
The burden of this research project consists of:
-Bruises after vena puncture.
We have already experience with this typr of research, see P02.050.
The participants experience it as not extemly painful or stressful.
Families in which an unclassified variant is identified experience considerable
psychological distress, not only due to the possibility that they may face a
cancer risk as high as that for known pathogenic mutations, but also due to the
uncertainty of this cancer risk. Reliable classification of UVs will
considerably increase the clinical utility and cost-effectiveness of DNA
testing and alleviate the psychological burden on these families.
Albinusdreef 2
Leiden 2300 RC
NL
Albinusdreef 2
Leiden 2300 RC
NL
Listed location countries
Age
Inclusion criteria
1) UV-cohort: patients who are carrier of an unclassified variant.
2) Affected relatives of the UV-cohort patients will be invited for this study.
3) At least one non-affected family member of the UV-cohort patients will be invited to take part in this study. ;The UV-cohort consists of patients diagnosed with a primary breast tumor before the age of 60 years and are unrelated.
The patient can be included if only one unclassified variant is found in the BRCA1 or BRCA2 gene.
All the participants should be older than 18 years, competent and independent of the researcher.
They should all be informed about the study, its goal and its duration.
They know about the possibility of interim quitting the study.
Exclusion criteria
Exclusion criteria:
- Younger than 18 years old and older than 60 years old. Not affected family members may however, be older than 60 years old.
-The participants should be competent to be able to make decision about participation.
Design
Recruitment
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL39318.058.12 |